Sex differences for major congenital heart defects in Down Syndrome: A population based study

Down syndrome (DS) is the most common autosomal chromosomal anomaly in liveborn infants. About 40% of infants with DS have a major congenital heart defect (CHD). Among them, atrioventricular septal defects (AVSD), atrial septal defects (ASD), ventricular septal defect (VSD) and Tetralogy of Fallot (ToF) are the most common. The aim of this study was to estimate the sex difference in the occurrence of CHD in infants with DS comparing it with non-DS infants.

Live birth cases of DS diagnosed by the first year of life were extracted from the Registry of Congenital Anomalies of Tuscany (2003-2015 period). CHDs associated with DS were detected both from the registry and the hospital discharge data. Sex differences in total CHDs and ASD, VSD, AVSD, severe CHDs, ToF subgroups were investigated. Relative Risks between males and females (RR_MF) with p-values and 95% confidence interval (95% CI) were estimated. RR_MF of CHD in infants with DS was compared to RR_MF in infants without DS. The ratio between relative risks (RRR) was estimated.

A total of 230 live birth cases of DS were analyzed, with a prevalence of 5.70 per 10,000 births. Sex ratio_MF was 1.3. One hundred and one DS cases (43.9%) were associated with at least one CHD. Among them, CHDs are more frequent in females (total CHD: RR_MF = 0.62; 95% CI: 0.46-0.83, ASD: RR_MF = 0.40; 95% CI: 0.21-0.77, severe CHD: RR_MF = 0.58; 95% CI: 0.35-0.95, AVSD: RR_MF = 0.57; 95% CI: 0.32-1.00, VSD: RR_MF = 0.59; 95% CI: 0.35-1.00). Four cases of ToF were observed (all males). Sex difference was more evident in DS than in non-DS infants (RRR = 0.63; 95% CI: 0.52-0.77), in particular for severe CHDs (RRR = 0.38; 95% CI: 0.25-0.57).

The increased sex difference for CHDs in DS suggests a possible role of sex as effect modifier in the association between DS and CHD. The results enforce the evidence on sex differences for CHDs in DS and can stimulate future genetic research activities.